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  1. Article ; Online: Causes of Phenotypic Variability and Disabilities after Prenatal Viral Infections.

    Kousa, Youssef A / Hossain, Reafa A

    Tropical medicine and infectious disease

    2021  Volume 6, Issue 2

    Abstract: Prenatal viral infection can lead to a spectrum of neurodevelopmental disabilities or fetal demise. These can include microencephaly, global developmental delay, intellectual disability, refractory epilepsy, deafness, retinal defects, and cortical-visual ...

    Abstract Prenatal viral infection can lead to a spectrum of neurodevelopmental disabilities or fetal demise. These can include microencephaly, global developmental delay, intellectual disability, refractory epilepsy, deafness, retinal defects, and cortical-visual impairment. Each of these clinical conditions can occur on a semi-quantitative to continuous spectrum, from mild to severe disease, and often as a collective of phenotypes. Such serious outcomes result from viruses' overlapping neuropathology and hosts' common neuronal and gene regulatory response to infections. The etiology of variability in clinical outcomes is not yet clear, but it may be related to viral, host, vector, and/or environmental risk and protective factors that likely interact in multiple ways. In this perspective of the literature, we work toward understanding the causes of phenotypic variability after prenatal viral infections by highlighting key aspects of the viral lifecycle that can affect human disease, with special attention to the 2015 Zika pandemic. Therefore, this work offers important insights into how viral infections and environmental teratogens affect the prenatal brain, toward our ultimate goal of preventing neurodevelopmental disabilities.
    Language English
    Publishing date 2021-06-01
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2414-6366
    ISSN (online) 2414-6366
    DOI 10.3390/tropicalmed6020095
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels.

    Prabhakar, Apurva T / James, Claire D / Youssef, Aya H / Hossain, Reafa A / Hill, Ronald D / Bristol, Molly L / Wang, Xu / Dubey, Aanchal / Morgan, Iain M

    bioRxiv : the preprint server for biology

    2024  

    Abstract: An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as ... ...

    Abstract An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes immortalized by HPV16 (HFK+HPV16). SIRT1 deacetylation reduces E2 protein stability and here we demonstrate that increased E2 acetylation occurs during mitosis in a TopBP1 interacting dependent manner, promoting E2 mitotic stabilization. p300 mediates E2 acetylation and acetylation is increased due to E2 switching off SIRT1 function during mitosis in a TopBP1 interacting dependent manner, confirmed by increased p53 stability and acetylation on lysine 382, a known target for SIRT1 deacetylation. SIRT1 can complex with E2 in growing cells but is unable to do so during mitosis due to the E2-TopBP1 interaction; SIRT1 is also unable to complex with p53 in mitotic E2 wild type cells but can complex with p53 outside of mitosis. E2 lysines 111 and 112 are highly conserved residues across all E2 proteins and we demonstrate that K111 hyper-acetylation occurs during mitosis, promoting E2 interaction with Topoisomerase 1 (Top1). We also demonstrate that K112 ubiquitination promotes E2 proteasomal degradation during mitosis. The results present a model in which the E2-TopBP1 complex inactivates SIRT1 during mitosis and E2 acetylation on K111 by p300 increases, promoting interaction with Top1 that protects K112 from ubiquitination and therefore E2 proteasomal degradation.
    Importance: Human papillomaviruses are causative agents in around 5% of all human cancers. While there are prophylactic vaccines that will significantly alleviate HPV disease burden on future generations, there are currently no anti-viral strategies available for the treatment of HPV cancers. To generate such reagents, we must understand more about the HPV life cycle, and in particular about viral-host interactions. Here we describe a novel mitotic complex generated by the HPV16 E2 protein interacting with the host protein TopBP1 that controls the function of the deacetylase SIRT1. The E2-TopBP1 interaction disrupts SIRT1 function during mitosis in order to enhance acetylation and stability of viral and host proteins. This novel complex is essential for the HPV16 life cycle and represents a novel anti-viral therapeutic target.
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.15.575713
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels and activates the DNA damage response.

    Prabhakar, Apurva T / James, Claire D / Youssef, Aya H / Hossain, Reafa A / Hill, Ronald D / Bristol, Molly L / Wang, Xu / Dubey, Aanchal / Karimi, Elmira / Morgan, Iain M

    mBio

    2024  , Page(s) e0067624

    Abstract: An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as ... ...

    Abstract An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes immortalized by HPV16 (HFK + HPV16). SIRT1 deacetylation reduces E2 protein stability and here we demonstrate that increased E2 acetylation occurs during mitosis in a TopBP1 interacting-dependent manner, promoting E2 mitotic stabilization. p300 mediates E2 acetylation and acetylation is increased due to E2 switching off SIRT1 function during mitosis in a TopBP1 interacting-dependent manner, confirmed by increased p53 stability and acetylation on lysine 382, a known target for SIRT1 deacetylation. SIRT1 can complex with E2 in growing cells but is unable to do so during mitosis due to the E2-TopBP1 interaction; SIRT1 is also unable to complex with p53 in mitotic E2 wild-type cells but can complex with p53 outside of mitosis. E2 lysines 111 and 112 are highly conserved residues across all E2 proteins and we demonstrate that K111 hyper-acetylation occurs during mitosis, promoting E2 interaction with Topoisomerase 1 (Top1). We demonstrate that K112 ubiquitination promotes E2 proteasomal degradation during mitosis. E2-TopBP1 interaction promotes mitotic acetylation of CHK2, promoting phosphorylation and activation of the DNA damage response (DDR). The results present a new model in which the E2-TopBP1 complex inactivates SIRT1 during mitosis, and activates the DDR. This is a novel mechanism of HPV16 activation of the DDR, a requirement for the viral life cycle.
    Importance: Human papillomaviruses (HPVs) are causative agents in around 5% of all human cancers. While there are prophylactic vaccines that will significantly alleviate HPV disease burden on future generations, there are currently no anti-viral strategies available for the treatment of HPV cancers. To generate such reagents, we must understand more about the HPV life cycle, and in particular about viral-host interactions. Here, we describe a novel mitotic complex generated by the HPV16 E2 protein interacting with the host protein TopBP1 that controls the function of the deacetylase SIRT1. The E2-TopBP1 interaction disrupts SIRT1 function during mitosis in order to enhance acetylation and stability of viral and host proteins. We also demonstrate that the E2-TopBP1 interaction activates the DDR. This novel complex is essential for the HPV16 life cycle and represents a novel anti-viral therapeutic target.
    Language English
    Publishing date 2024-05-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.00676-24
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: In silico modeling of epigenetic-induced changes in photoreceptor cis-regulatory elements.

    Hossain, Reafa A / Dunham, Nicholas R / Enke, Raymond A / Berndsen, Christopher E

    Molecular vision

    2018  Volume 24, Page(s) 218–230

    Abstract: Purpose: DNA methylation is a well-characterized epigenetic repressor of mRNA transcription in many plant and vertebrate systems. However, the mechanism of this repression is not fully understood. The process of transcription is controlled by proteins ... ...

    Abstract Purpose: DNA methylation is a well-characterized epigenetic repressor of mRNA transcription in many plant and vertebrate systems. However, the mechanism of this repression is not fully understood. The process of transcription is controlled by proteins that regulate recruitment and activity of RNA polymerase by binding to specific cis-regulatory sequences. Cone-rod homeobox (CRX) is a well-characterized mammalian transcription factor that controls photoreceptor cell-specific gene expression. Although much is known about the functions and DNA binding specificity of CRX, little is known about how DNA methylation modulates CRX binding affinity to genomic cis-regulatory elements.
    Methods: We used bisulfite pyrosequencing of human ocular tissues to measure DNA methylation levels of the regulatory regions of
    Results: In this study, we demonstrate an inverse correlation between DNA methylation in regulatory regions adjacent to the human
    Conclusions: Collectively, these data demonstrate epigenetic regulation of CRX binding sites in human retinal tissue and provide insight into the mechanism of this mode of epigenetic regulation to be tested in future experiments.
    MeSH term(s) Acute-Phase Proteins/chemistry ; Acute-Phase Proteins/genetics ; Acute-Phase Proteins/metabolism ; Base Sequence ; Cadaver ; Cyclic Nucleotide Phosphodiesterases, Type 6/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism ; DNA Methylation ; Epigenesis, Genetic ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Long Interspersed Nucleotide Elements ; Models, Molecular ; PAX6 Transcription Factor/genetics ; PAX6 Transcription Factor/metabolism ; Photoreceptor Cells, Vertebrate/cytology ; Photoreceptor Cells, Vertebrate/metabolism ; Promoter Regions, Genetic ; Protein Binding ; Sequence Alignment ; Sequence Homology, Nucleic Acid ; Trans-Activators/chemistry ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcription, Genetic
    Chemical Substances Acute-Phase Proteins ; Homeodomain Proteins ; PAX6 Transcription Factor ; PAX6 protein, human ; Trans-Activators ; acute-phase protein rho ; cone rod homeobox protein ; Cyclic Nucleotide Phosphodiesterases, Type 6 (EC 3.1.4.35) ; PDE6B protein, human (EC 3.1.4.35)
    Language English
    Publishing date 2018-03-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2017540-1
    ISSN 1090-0535 ; 1090-0535
    ISSN (online) 1090-0535
    ISSN 1090-0535
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Structural insights into hepatitis C virus receptor binding and entry.

    Kumar, Ashish / Hossain, Reafa A / Yost, Samantha A / Bu, Wei / Wang, Yuanyuan / Dearborn, Altaira D / Grakoui, Arash / Cohen, Jeffrey I / Marcotrigiano, Joseph

    Nature

    2021  Volume 598, Issue 7881, Page(s) 521–525

    Abstract: Hepatitis C virus (HCV) infection is a causal agent of chronic liver disease, cirrhosis and hepatocellular carcinoma in humans, and afflicts more than 70 million people worldwide. The HCV envelope glycoproteins E1 and E2 are responsible for the binding ... ...

    Abstract Hepatitis C virus (HCV) infection is a causal agent of chronic liver disease, cirrhosis and hepatocellular carcinoma in humans, and afflicts more than 70 million people worldwide. The HCV envelope glycoproteins E1 and E2 are responsible for the binding of the virus to the host cell, but the exact entry process remains undetermined
    MeSH term(s) Animals ; Antibodies, Neutralizing/immunology ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; HEK293 Cells ; Hepacivirus/chemistry ; Hepacivirus/genetics ; Hepacivirus/metabolism ; Humans ; Leontopithecus ; Membrane Fusion ; Models, Molecular ; Protein Binding ; Receptors, Virus/chemistry ; Receptors, Virus/immunology ; Receptors, Virus/metabolism ; Tetraspanin 28/chemistry ; Tetraspanin 28/immunology ; Tetraspanin 28/metabolism ; Viral Envelope Proteins/chemistry ; Viral Envelope Proteins/metabolism ; Virus Internalization
    Chemical Substances Antibodies, Neutralizing ; CD81 protein, human ; Receptors, Virus ; Tetraspanin 28 ; Viral Envelope Proteins ; glycoprotein E2, Hepatitis C virus (157184-61-7)
    Language English
    Publishing date 2021-09-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-021-03913-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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